CN1857730B - Multi-cavity degradable implantable drug release carrier with micropores and its preparation process - Google Patents

Abstract

The present invention proposes a multi-cavity degradable implantable controlled-release drug carrier system with micropores, which realizes long-term linear drug release through the joint effect of drug penetration and degradation diffusion. The carrier structure is made of degradable material polylactic acid-glycolic acid (PLGA), which can be absorbed by the human body under the action of body fluids and biological enzymes without taking it out, reducing the pain of patients. The drug release system is mainly suitable for water-soluble drugs. According to the molecular weight of the drug, the release rate and period can be adjusted by rationally designing the size, number and distribution of micropores, and by selecting the degradation characteristic parameters of the material. The microporous structure and multi-cavity structure of the present invention overcome the initial drug release hysteresis and mid-term burst release phenomenon existing in the existing implantable sustained-release drug delivery system, and is a long-acting constant drug with large drug loading and good adjustability. Rapid controlled release drug delivery system.

Description

Multi-cavity degradable implantable drug release carrier with micropores and its preparation process

technical field

The invention belongs to the field of medicine and chemical industry, and in particular relates to a multi-cavity degradable implantable controlled-release drug carrier with micropores and a preparation process thereof.

Background technique

The types of conventional medicaments are divided into traditional oral preparations, injection injections, external application ointments, etc. In addition, there are implantable long-term controlled release preparations. Regardless of the form, it is generally a matrix-type pharmaceutical preparation system in which the drug and adjuvant are mixed, that is, the drug is uniformly dissolved or dispersed in the drug adjuvant or carrier material, which not only has a low active ingredient , and it is usually expressed as a "first-order" drug release characteristic, that is, there is a sudden release of the drug during the drug release period, resulting in a large change in the blood drug concentration of the drug user.

The traditional way of drug administration is generally short-acting periodic drug administration. There is a burst release phenomenon in the early stage of drug administration, causing the blood drug concentration to exceed the toxic level. After that, the drug release rate gradually decreases, and the final blood drug concentration is lower than the therapeutic level. Therefore, regular supplementation is required. medicine. For tablet oral preparations, it generally belongs to the diffusion type drug release. The drug enters the digestive system to be absorbed, and then releases to the blood system through the liver. At the same time, a considerable part of the drug is excreted from the digestive tract, so the bioavailability is low. . For injection drugs, they are released by direct injection, have high bioavailability and quick effect, but often cause pain and inconvenience to patients. For biopharmaceuticals such as proteins, the above-mentioned traditional drug delivery methods often cannot meet the medical requirements very well, so a preparation form that can release drugs at a long-term constant rate is needed.

Controlled sustained-release preparations can achieve long-term stable drug administration, greatly reduce the number of times patients take drugs, and improve patient compliance and therapeutic effects. It has become a research hotspot in the field of medicine in recent years. There are several types of skin release and implantable. The oral type mainly includes various sustained-release capsules. There are a large number of sustained-release microspheres prepared by mixing degradable materials and drugs in the capsules. The drugs are encapsulated in the capsule according to the release time. Different degradable films mainly release drugs through the diffusion mechanism to reduce the drug burst release effect and prolong the drug release time. However, because the drug is still administered through the digestive tract, it is impossible to achieve a longer drug release cycle in the body, generally the longest The medicine is taken once every 24 hours, so that patients can reduce the number of daily doses. Transdermal preparations are mainly administered through external application, and the focus of research is how to effectively release macromolecular drugs into the subcutaneous. The implantable type mainly includes various osmotic pumps. The depot-based preparations mainly control the drug release rate through osmotic and semi-osmotic mechanisms to ensure long-term stable blood drug concentration. The latest research results also include implantable drug delivery devices with automatic control functions prepared by MEMS technology. Drug system, through the micro-control system to periodically open the sealing cover of the drug storage in the body, to release the drug regularly and quantitatively. However, the biggest defect of this drug delivery system is that after the drug is released, the system needs to be taken out again, which brings new benefits to the patient. Sustained-release preparations made of biodegradable materials are the mainstream of implantable drug delivery systems. At present, the most commonly used is to uniformly mix degradable materials and drugs to make tablets, and implant them into the body near the lesion. Gradually degrade the carrier material to carry out sustained and controlled drug release. However, this type of preparation still generally has the phenomenon of initial drug release hysteresis and burst release. In addition, due to drug saturation, the active ingredients in the preparation generally do not exceed 20%, and the maximum The biggest problem is that when the physical and chemical properties of the drug and the carrier material do not match, the preparation cannot be realized. Therefore, a new dosage form is to use degradable materials to prepare a cavity-type sustained-release carrier system, and the drug is encapsulated in multiple microcavities. In the body, as the carrier material degrades, the microcavity breaks and releases the drug one by one, which plays a sustained release role. This carrier system can not only greatly increase the effective content of the drug, but also is suitable for any drug. Multi-cavity sealing drugs can be better However, since the drug release cycle is restricted by the degradation cycle of the carrier material, the corresponding initial drug release hysteresis is also closely related to this, that is, the longer the sustained release cycle, the longer the initial drug release lag time. This is a pair of complementary contradictions. How to achieve long-term stable drug release and eliminate the hysteresis of initial drug release as much as possible is one of the key issues in developing this type of implantable sustained-release system and improving its clinical performance.

Contents of the invention

The purpose of the present invention is to overcome the above-mentioned shortcomings of the prior art, and to provide a preparation process of a microporous multi-cavity degradable implantable controlled-release drug carrier that is simple and can realize rapid linear drug release.

In order to achieve the above-mentioned purpose, the technical scheme adopted in the present invention is: first adopt deep ultraviolet lithography and electroplating process to process the polydimethylsiloxane mold of medicine controlled release carrier on silicon chip; Preparation of polylactic acid-polyglycolic acid copolymer, polylactic acid or polyanhydride drug controlled release carrier and encapsulation film, the drug controlled release carrier has a drug-loading cavity with a structural size of 500-2000 μm and a depth of 50-2000 μm. The distance between drug cavities, that is, the wall thickness is 10-80 μm, and the thickness of the packaging film is 50-200 μm due to different materials; the drug is placed in the drug-loading cavity of the drug-controlled release carrier and the surface of the drug-controlled release carrier is cleaned. The powder of the drug; the polydimethylsiloxane microneedle mold for preparing the microneedle is processed by deep ultraviolet lithography and electroplating technology, and the microneedle with the required diameter is prepared by electroplating using the microneedle mold; the packaging film is fixed on the soft support On the above, the porous film is obtained by puncturing the encapsulation film with micro-needles; the porous film is placed on the drug-containing drug-controlled release carrier, and then hot-pressed and encapsulated.

The invention comprises a drug controlled release carrier and a porous film obtained by puncturing a microneedle packaging film arranged on it. The drug-loaded cavity of the drug controlled release carrier has a structural size of 500-2000 μm and a depth of 50-2000 μm. The distance between the two drug-loading cavities, that is, the wall thickness is 10-80 μm, and the thickness of the packaging film is 50-200 μm due to different materials.

The present invention combines MEMS technology and rapid prototyping technology, processes and prepares the mold of carrier and microneedle; With biodegradable medical polymer material (such as polylactic acid-polyglycolic acid copolymer (PLGA), polylactic acid (PLA) and polyanhydride ( CPP-SA) etc.) prepare corresponding multi-cavity carrier structures for the object, and fill the inside with drugs; through microneedle combination molds with different diameters, groups of micropores are processed on the surface of the carrier, and the size of the pores depends on the released drugs. The size of the molecular weight and the combination of micropores depend on the drug release period and initial drug release rate required by different drugs; at the same time, the average drug release rate can be further regulated by optimizing the design of the carrier's structural form and selecting material properties, which can effectively improve the previous drug release. The initial stagnation of drug release and the phenomenon of burst release in the mid-term of quasi-sustained-release preparations can achieve the goal of uniform and stable drug release throughout the cycle.

Description of drawings

Fig. 1 is a preparation process flow chart of the present invention;

Fig. 2 is a schematic structural view of a drug controlled release carrier 2 of the present invention;

Fig. 3 is a structural diagram of the microporous drug controlled release carrier of the present invention;

Fig. 4 is the drug release curve of the multi-cavity carrier controlled-release preparation with micropores, wherein the abscissa is time, and the ordinate is cumulative drug release;

Fig. 5 is the drug release curve of the multi-cavity carrier controlled-release preparation without micropores, wherein the abscissa is time, and the ordinate is cumulative drug release;

Fig. 6 is the drug release curve of the single cavity carrier controlled-release preparation with micropores, where the abscissa is time, and the ordinate is the cumulative drug release.

Detailed ways

Embodiment 1, referring to Fig. 1, at first adopt deep ultraviolet lithography and electroplating process UV-LIGA to process the polydimethylsiloxane (PDMS) mold 1 of preparation carrier on silicon wafer; Utilize evaporation solvent method then on mold 1 Prepare polylactic acid-polyglycolic acid copolymer, polylactic acid or polyanhydride drug-controlled release carrier 2 and encapsulation film 5, the drug-loaded cavity 3 of the drug-controlled release carrier 2 has a structural size of 500-2000 μm and a depth of 50-50 μm 2000 μm, the distance between the two drug-carrying cavities 3, that is, the wall thickness 4 is 10-30 μm, as shown in Figure 2, and the thickness of the packaging film 5 is 50-200 μm; for the preparation of the carrier structure, injection molding or molding methods can also be used, especially Molding method, prepare corresponding mold, just can mass-produce rapidly, and efficiency is very high; Drug 6 is placed in the drug-carrying cavity 3 of drug controlled release carrier 2 and cleans up the drug powder adhered on the surface of drug controlled release carrier 2, so as to avoid Affect packaging; use deep ultraviolet lithography and electroplating process UV-LIGA to prepare microneedles 7 with required diameters; fix polylactic acid-polyglycolic acid copolymer, polylactic acid or polyanhydride encapsulation film 5 on a soft support, and pass microneedles 7. Perforate the packaging film 5, or use laser drilling and chemical methods to make holes to obtain a porous film 8; place the porous film 8 on the drug-containing polylactic acid-polyglycolic acid copolymer, polylactic acid or polyanhydride drug On the controlled-release carrier 2, heat-press encapsulation is performed to prepare a multi-cavity degradable implantable controlled-release preparation with micropores, as shown in Figure 3, to achieve long-term linear release of the drug.

On the basis of the multi-chamber slow-release system, the present invention proposes a new drug release mode combining percolation diffusion and degradation diffusion: a set of microchamber carriers is regularly designed on the surface of the multi-chamber carrier made of biodegradable polymer materials. Micropores, so that part of the drug cavity has half-through or full-through micropores with different pore sizes, and part of the cavity is still a closed cavity. When it is implanted in the body, the porous cavity first absorbs the body fluid, so that the drug in the cavity is dissolved, and at the same time, the carrier material swells due to water absorption, making the pore size smaller to form permeable or semi-permeable pores, so that the drug will not leak out directly. , but released in osmotic form. Then as the material degrades, the cavity with semi-through holes also begins to osmotically release the drug, and the final step is the diffusion release and degradation drug release of the closed cavity. Through the organic combination of these three different drug release mechanisms, the drug release hysteresis of general biodegradable materials can be effectively avoided, and a more stable drug release curve can be formed at the same time.

Two kinds of prepared drug carrier controlled-release preparations with micropores were implanted in normal saline (37° C.) and carried out in vitro drug release test, and the amount of drug release was detected by a UV-visible spectrophotometer (wavelengths were respectively λ=246nm and λ= 264nm), the drug release curve is shown in Figure 4, it can be seen that the two drug carrier preparations have no initial stagnation and burst release during the drug release process, and the linearity of the cumulative drug release is better.

Using the method of the present invention, the controlled-release drug carrier 2 is filled with paracetamol and chlorpheniramine respectively, and then hot-pressed and encapsulated to prepare a multi-cavity degradable carrier-controlled release preparation, but without microporous treatment, the two The carrier controlled-release preparation of the drug was carried out in vitro drug release test in normal saline (37° C.), and the amount of drug release was detected by a UV-visible spectrophotometer (wavelengths were λ=246nm and λ=264nm), and the drug release curve was shown in Figure 5 It can be seen that there is an initial stagnation phenomenon in the drug release process of the multi-cavity carrier controlled-release preparation without micropores, and the total amount of drug released after 40 days is less than 8%, which seriously affects the therapeutic effect of the drug.

Utilize single-cavity medicine controllable release carrier 2 and encapsulation film 5, carry out perforation to encapsulation film 5, obtain porous film 8, then fill acetaminophen and chlorpheniramine respectively to drug carrier, carry out thermocompression encapsulation with porous film 8, It is prepared as a single-cavity degradable carrier controlled-release preparation with micropores. The carrier controlled-release preparation of these two kinds of medicines is carried out in vitro drug release test in normal saline (37 ℃), and drug release amount is detected by ultraviolet-visible spectrophotometer (wavelength is respectively λ=246nm and λ=264nm), and drug release curve is as follows As shown in Figure 6, it can be seen that the single-chamber controlled-release preparation of the same carrier has an initial burst release phenomenon, and the duration of drug release is short, showing a first-order release form.

The present invention adopts the characteristics of micromachine manufacturing MEMS technology and rapid prototyping technology, processes and prepares the PDMS mold of such carriers and micropores, and can quickly manufacture carriers and microneedles by using injection molding and electroplating methods; biodegradable medical polymers Such carriers prepared for materials (such as polylactic acid-polyglycolic acid copolymer (PLGA), polylactic acid (PLA) and polyanhydride (CPP-SA), etc.), can be filled with drugs inside to achieve linear release, and the carrier’s Large drug loading capacity and long-lasting efficacy. This carrier is suitable for most water-soluble drugs. By preparing microneedles with different diameters, micropores with different diameters can be processed according to needs to meet the drug release rate required by different drugs. At the same time, it can By changing the structural form and material properties of the carrier to assist in regulating the release rate of the drug, the phenomenon of stagnant drug release and burst release in the past drug preparations has been changed.

Claims (2)

1. be with the preparation technology of the multi-cavity body degradable implanted medicine controlled release carrier of micropore, it is characterized in that:

1) at first adopts the polydimethylsiloxane mould (1) of deep-UV lithography and electroplating technology processing and preparing medicine controlled release carrier on silicon chip;

2) utilize the evaporating solvent method to go up the medicine controlled release carrier (2) and the packaging film (5) of preparation polylactic acid-polyglycolic acid copolymer, polylactic acid or poly-anhydride at mould (1) then, the physical dimension of the medicine carrying cavity (3) of this medicine controlled release carrier (2) is 500～2000 μ m, the degree of depth is 50～2000 μ m, spacing between the two medicine carrying cavitys (3) is that wall thickness (4) is 10～80 μ m, and the thickness of packaging film (5) is because of 50～200 μ m that do not coexist of material;

3) medicine (6) is placed in the medicine carrying cavity (3) of medicine controlled release carrier (2) and clean out the medicated powder of medicine controlled release carrier (2) surface adhering;

4) adopt deep-UV lithography and electroplating technology to process the polydimethylsiloxane micropin mould (1`) of preparation micropin, utilize micropin mould (1`) to adopt and electroplate the micropin (7) of preparing required diameter;

5) packaging film (5) is fixed in the soft support, packaging film (5) is pricked the hole, obtain porous membrane (8) by micropin (7);

6) porous membrane (8) is placed on the medicine controlled release carrier (2) of pastille, carries out packaging by hot pressing and get final product.

2. the medicine controlled release carrier that makes according to the described preparation technology of claim 1, it is characterized in that: comprise that medicine controlled release carrier (2) and the micropin (7) that passes through disposed thereon prick the porous membrane (8) that the hole obtains to packaging film (5), the physical dimension of the medicine carrying cavity (3) of this medicine controlled release carrier (2) is 500～2000 μ m, the degree of depth is 50～2000 μ m, spacing between the two medicine carrying cavitys (3) is that wall thickness (4) is 10～80 μ m, and the thickness of packaging film (5) is because of 50～200 μ m that do not coexist of material.

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